Huang Ze-Nan, Wang Jing, Wang Ze-Yu, Min Ling-Yuan, Ni Hai-Ling, Han Yan-Ling, Tian You-Yue, Cui Ya-Zhou, Han Jing-Xiang, Cheng Xiao-Fei
Department of Orthopedics, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 200072, Shandong Province, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 200072, Shandong Province, China.
iScience. 2024 Apr 16;27(5):109733. doi: 10.1016/j.isci.2024.109733. eCollection 2024 May 17.
Intervertebral disc is a highly rhythmical tissue. As a key factor linking biorhythm and inflammatory response, the shielding effect of NR1D1 in the process of intervertebral disc degeneration remains unclear. Here, we first confirmed that NR1D1 in the nucleus pulposus tissue presents periodic rhythmic changes and decreases in expression with intervertebral disc degeneration. Second, when NR1D1 was activated by SR9009 , NLRP3 inflammasome assembly and IL-1β production were inhibited, while ECM synthesis was increased. Finally, the vivo experiments further confirmed that the activation of NR1D1 can delay the process of disc degeneration to a certain extent. Mechanistically, we demonstrate that NR1D1 can bind to IL-1β and NLRP3 promoters, and that the NR1D1/NLRP3/IL-1β pathway is involved in this process. Our results demonstrate that the activation of NR1D1 can effectively reduce IL-1β secretion, alleviate LPS-induced NPMSC pyroptosis, and protect ECM degeneration.
椎间盘是一种具有高度节律性的组织。作为连接生物节律与炎症反应的关键因素，NR1D1在椎间盘退变过程中的保护作用仍不清楚。在此，我们首先证实髓核组织中的NR1D1呈现周期性节律变化，且其表达随椎间盘退变而降低。其次，当用SR9009激活NR1D1时，NLRP3炎性小体组装和IL-1β生成受到抑制，而细胞外基质（ECM）合成增加。最后，体内实验进一步证实，激活NR1D1可在一定程度上延缓椎间盘退变进程。机制上，我们证明NR1D1可与IL-1β和NLRP3启动子结合，且NR1D1/NLRP3/IL-1β通路参与此过程。我们的结果表明，激活NR1D1可有效减少IL-1β分泌，减轻脂多糖诱导的髓核间充质干细胞焦亡，并保护ECM退变。
